High CTLA-4 expression correlates with poor prognosis in thymoma patients.

Giorgio Santoni,Rossana Berardi,Giovanni Bernardini,Vittorio Paolucci,Silvia Rinaldi,Maria Beatrice Morelli,Daniele Tomassoni,Matteo Santoni,Massimo Nabissi,Claudio Cardinali,Oliviero Marinelli,Consuelo Amantini,Mariangela Torniai,Francesca Morgese

doi:10.18632/oncotarget.24645

Abstract

Thymomas, tumors that arise from epithelial cells of the thymus gland, are the most common neoplasms of the anterior mediastinum, with an incidence rate of approximately 2.5 per million/year. Cytotoxic T Lymphocyte Antigen 4 (CTLA-4 or CD152) exerts inhibitory activity on T cells, and since its oncogenic role in the progression of different types of tumors, it has emerged as a potential therapeutic target in cancer patients.In this study, we assessed the expression of CTLA-4 both at mRNA and protein levels in paraffin embedded-tissues from patients with thymomas. Furthermore, we evaluated the relationship between CTLA-4 expression and the clinical-pathologic characteristics and prognosis in patients with thymomas. Sixty-eight patients with median age corresponding to 62 years were included in this analysis. Thymomas were classified accordingly to the WHO and Masaoka-Koga for histochemical analysis and for prognostic significance.A statistical difference was found between CTLA-4 mRNA levels in human normal thymus compared with thymoma specimens. CTLA-4 expression was statistically found to progressively increase in A, B1, B2, AB and it was maximal in B3 thymomas. According to Masaoka-Koga pathological classification, CTLA-4 expression was lower in I, IIA and IIB, and higher in invasive III and IV stages. By confocal microscopy analysis we identified the expression of CTLA-4 both in tumor cells and in CD45+ tumor-infiltrating leukocytes, mainly in B3 and AB thymomas.Finally, CTLA-4 overexpression significantly correlates with reduced overall survival in thymoma patients and in atypical thymoma subgroup, suggesting that it represents a negative prognostic factor.

Highlights

Thymomas, tumors that arise from epithelial cells of the thymus gland, are the most common neoplasms of the anterior mediastinum, with an incidence rate of approximately 2.5 per million/year [1]
We evaluated the correlation between CTLA-4 expression and clinico-pathologic characteristics and prognosis of patients with thymomas
The management of Thymic epithelial tumors (TETs) within clinical practice is based on a multimodal therapeutic strategy including surgery, chemotherapy and radiotherapy with a multidisciplinary approach and prognostic evaluation mainly based on Masaoka-Koga staging and WHO classification [39,40,41]

Summary

Introduction

Tumors that arise from epithelial cells of the thymus gland, are the most common neoplasms of the anterior mediastinum, with an incidence rate of approximately 2.5 per million/year [1]. Once a tumor has been assigned to a differentiation category of thymic epithelial neoplasms, reliable prognostication can be determined by clinical and pathological Masaoka-Koga staging of the lesions. About forty percent of the thymoma patients had associated MG, and preoperative absence of MG has been considered an independent predictor of poorer overall survival (OS) [12]. This disease is caused by an autoimmune reaction against components of the neuromuscular junction on the post-synaptic membrane of the striated skeletal muscles [13] and it is present at first diagnosis in up to a third of thymoma patients [14]

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Conclusion